1. Field of the Invention
This invention relates in general to mass spectrometry (MS) especially to mass spectrometry utilizing multipole ion guides, and in particular to orthogonal acceleration (oa) time-of-flight (TOF) MS. More specifically, this invention relates to a configuration and a method of using multipole ion guide to transport and focus ions into a mass analyzer.
2. Description of the Related Art
Over the last decade, mass spectrometry has played an increasingly important role in the identification and characterization of various biochemical compounds in research laboratories and various industries. The speed, specificity, and sensitivity of mass spectrometry make spectrometers especially attractive for requiring rapid identification and characterization of biochemical compounds. Mass spectrometric configurations are distinguished by the methods and techniques utilized for ionization and separation of the analyte molecules. The mass separation process can include techniques for ion isolation, subsequent molecular fragmentation, and mass analysis of the fragment ions. The pattern of fragmentation yields information about the structure of the analyte molecules introduced into the mass spectrometer. The technique of combining ion isolation, molecular fragmentation, and mass analysis is referred to in the art as tandem (or MS/MS) mass spectrometry.
Atmospheric pressure ion sources have become increasingly important as a tool for generating ions used in mass analysis. Electrospray ionization (ESI), Atmospheric Pressure Chemical Ionization (APCI), and Inductively Couple Plasma (ICP) ion sources produce ions from analyte species at atmospheric pressure. Once produced, ions can be transported into a vacuum of mass spectrometer using an atmospheric pressure interface. In addition to ESI (see Yamashita, M.; Fenn, J. B. J. Chem. Phys. 1984, 88: 4451 and Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C. M. Science 1989, 246: 64, the entire contents of which are incorporated herein by reference), another known technique for producing gas phase ions of large biomolecules is matrix-assisted laser desorption/ionization (MALDI—see Karas, M; Hillenkamp, F.; Anal. Chem. 1988, 60, 2299–2301, the entire contents of which are incorporated herein by reference). ESI and MALDI are characterizable as soft ionization techniques of large biomolecules. ESI produces multiply-charged molecular ions while MALDI produces mostly singly-charged ions. ESI continuously produces ions at normal atmospheric conditions while MALDI is a pulsed ionization method. Liquid separation techniques such as, for example, high pressure liquid chromatography (HPLC), chemical electrospray (CE), and recently developed electrochromatography coupled on-line with ESI mass spectrometry have made major contributions to the success of modern biochemistry, pharmacology and health sciences.
Until recently, MALDI was mostly used for producing ions under vacuum conditions. An atmospheric pressure matrix-assisted laser desorption/ionization (AP-MALDI) source (Laiko et al. U.S. Pat. No. 5,965,884, the entire contents of which are incorporated herein by reference) produces ions of biomolecules under normal atmospheric pressure conditions. AP-MALDI ions are then introduced into a mass spectrometer using an atmospheric pressure interface similar to that used for introduction of ESI ions.
Known techniques for analyzing ion masses include: sector magnetic instruments, quadrupole mass spectrometers, quadrupole ion trap mass spectrometers, time-of-flight (TOF) mass spectrometers, orthogonal acceleration (oa) TOF-MS, Fourier transform ion cyclotron resonance mass spectrometers (FTICR-MS). Radio frequency (RF) ion guides are widely used for delivering ions from the atmosphere side to the vacuum inside mass spectrometers as well as for transporting ions from one point in space to another point of space within the vacuum of a mass spectrometer. A trapping field in the transverse direction of an ion guide can be created by applying an alternating RF voltages to the ion guide electrodes. Ion guides can include single or multiple sections of parallel rods to which the alternative RF voltages can be applied. Ion guides are typically designated according to the number of the rods used in the section: quadrupoles, hexapoles, octopoles, or multipoles if four, six, eight, or more rods are used. In the ion guides, RF voltages are applied to neighboring rods in each section with a shifted phase (normally shifted by 180°).
Another way of making ion guide sections is to place a series of circular electrodes, each with a hole in the center, in a stack. When the RF voltage (shifted by 180° for adjacent electrodes) is applied, the ions are confined near the central axis of the stack. A wall with an aperture (referred to as a conductance limit) can separate the sections so that a different pressure can be maintained within any section.
Collisions with buffer gas molecules in ion guides sections can facilitate damping ion excessive energy so that the temperature of ions after several collisions may be close to the room temperature (295 K). A typical pressure of the buffer gas in the ion guide is the range of 0.1–100 mTorr, but can be lower or substantially higher as in an ion funnel. (See for example Smith et al, U.S. Pat. No. 6,107,628, the entire contents of which are incorporated herein by reference, which represents one more ion guide design).
In addition to operation as an ion guide, a quadrupole can operate in a mass filter mode. See, for example, Langmuir U.S. Pat. No. 3,334,225, the entire contents of which are incorporated herein by reference. In a mass filter mode, one of the ion guide quadrupole sections is normally tuned to pass ions within a selected m/z range that is required for operation in the above-noted tandem MS mode.
The ion energy within an ion guide section can be controlled by adjusting a DC voltage along the ion guide axis and/or by adjusting the trapping voltage on separate sections. By adjusting the DC voltage along the ion guide center (which can be done by floating sections at different DC voltages or using other mechanisms as described in Thomson et al. U.S. Pat. No. 5,847,386, the entire contents of which are incorporated herein by reference) one can drift ions through the buffer gas, thus heating internal degrees of freedom of the ions and even causing the ion dissociation. Fragmenting ions in the ion guides by collisional dissociation is widely used in tandem mass spectrometry.
In addition to a transmission mode in which ions are transported from one place to another, the ion guide can also work in an ion trap mode. See Dresh et al., U.S. Pat. No. 5,689,111, the entire contents of which are incorporated herein by reference. In an ion trap mode, the DC potentials on the conductance limits or on the adjacent ion guide sections are raised (for positive ions) to confine ions within the selected section. The trapped ions can then be manipulated within such a trap. Such manipulation of the ions can result in ion isolation, fragmentation and analysis. These operational modes are widely used in commercial instruments, such as for example, in Thermo Finnigan (Santa Clara, Calif.) LTQ™ mass spectrometer.
One triple quadrupole mass spectrometer (MS) can be a tandem mass spectrometer interfaced with an electrospray ion source. A triple quadrupole mass spectrometer includes three (normally quadrupole) sections that are used for ion isolation, fragmentation, and mass analysis. Triple quadrupole MS offers medium resolution (up to several thousands) and low mass range (up to 2000–3000 Da) for MS/MS analysis more sections can be added for auxiliary purposes. To overcome these limitations, hybrid quadrupole time of flight (Q-TOF or QqTOF where Q and q denote quadrupole sections operating as an ion filter and ion guide, respectively) instruments were developed. These techniques have been described for example by Morris et al., in Rapid Commun. Mass Spectrometry, 1996, 10:889–896, and by Shevchenko et al., Rapid Commun. Mass Spectrom. 1997, 11:1015–1024, the entire contents of which are incorporated herein by reference. The QqTOF configuration can be considered as a replacement of the third quadrupole in a triple quadrupole instrument by an orthogonal acceleration (oa)-TOF mass analyzer. Compared to a quadrupole analyzer, an orthogonal acceleration TOF mass spectrometer is a high resolution and high mass accuracy instrument (see for example, Mirgorodskaya, O. A.; Shevchenko, A. A.; Chernushevich, I. V.; Dodonov, A. F.; Miroshnikov, A. I., Anal. Chem. 66 (1994) 99; and Verentchikov, A. N.; Ens, W.; Standing, K. G., Anal. Chem. 66 (1994) 126, the entire contents of which are incorporated herein by reference). Because of the high mass accuracy provided by an oa-TOF instrument, it is valuable even in the normal MS mode, without the necessity of ion isolation and fragmentation sections in an ion guide (like in a commercial AccuTOF ESI-oa-TOF instrument from JEOL USA, Peabody, Mass.). The benefits of the QqTOF system are high sensitivity, mass resolution, and mass accuracy in both precursor (MS) and product ion (MS/MS) modes. A particular advantage for full-scan sensitivity (over a wide mass range) is provided in both modes by the parallel detection feature available in time-of-flight mass analyzer.
A high resolution in oa-TOF instruments is achieved using the orthogonal extraction of ions from the ion beam with a small spatial and velocity spread in the “time of flight” direction. The beam is usually formed from ions released from the ion guide by accelerating the ions to an energy of about 20 eV, and focusing and shaping the ion beam to make the beam divergence properties close to a parallel beam. This translates to a very high mass resolution (up to 20,000) and mass accuracy (down to few ppm) obtained in this kind of instruments. However, the high quality of the beam is usually achieved at the expense of instrument sensitivity since many ions are cut off of the beam to make a narrow ion distribution in the phase (i.e., the coordinate and velocity) space. For this reason, designing oa-TOF and QqTOF instruments always implies a trade-off between the sensitivity and mass resolution. Achieving both high sensitivity and high mass resolution/accuracy is one of practical and theoretical considerations.
Generating high quality ion beams (i.e., beams having a narrow spatial and velocity spreads) is also important in other MS instruments (see H. Wollnik, J. Mass Spectrom, 1999, 34: 991–1006, the entire contents of which are incorporated herein by reference). As an example, the capture of injected ions into a quadrupole ion trap can be substantially increased if ions are narrowly packed in the afore-mentioned phase space (see, for example, Doroshenko, V. M.; Cotter, R. J., J Mass Spectrom. 33 (1998) 305, the entire contents of which are incorporated herein by reference). Similar trapping problem exists in Fourier transform ion cyclotron resonance (FTICR) traps (M. V. Gorshkov, C. D. Masselon, G. A. Anderson, H. R. Udseth, R. D. Smith, Rapid Comm. Mass Spectrom., 2001, 15: 1558–1561, the entire contents of which are incorporated herein by reference).